Rapidly soluble film preparation

ABSTRACT

Disclosed is a rapidly soluble film preparation mainly comprising a drug, an edible polymer and a saccharide, a manufacturing method of which is simple, and having high elution rate.

TECHNICAL FIELD

The present invention relates to a film preparation (film-shaped drug)rapidly soluble in the oral cavity, and more particularly to a rapidlysoluble film preparation for oral administration containing a saccharidein a base, for the purpose of allowing a drug to be mainly absorbed intothe digestive organs by rapidly dissolving the drug in the oral cavity.

BACKGROUND ART

At present, as the drugs orally administered, naked tablets, coatedtablets, capsules, powders, granules, pills and aqueous drugs(solutions) have been put on the market. Then, the preparations for oralapplication include buccal tablets and mucosa-adhesive filmpreparations. However, these are ones in which the drugs are allowed tobe absorbed through the mucous membranes in the oral cavity, or ones forthe purpose of treatment of diseases in the oral cavity, and are notones for the purpose of usual drug absorption into the digestive tracts.Almost all of these are contrived to continuously release the drugs, andno rapidly soluble ones have been known.

Drugs commercially available as merely film-shaped, tape-shaped orsheet-shaped ones, not adhesive to the mucous membranes in the oralcavity, are not found. However, as seen from documents (patents), (A) asheet-shaped administration formation such as medicine, confectionery,other food, a cosmetic or an article similar thereto orally administeredor incorporated, which comprises 20 to 60% by weight of at least onefilm forming agent, 2 to 40% by weight of at least one gel formingagent, 0.1 to 35% by weight of at least one active substance (drug) andfurther less than 40% by weight of at least one inactive filler, andrapidly decomposes in water (Toku-Kai-Hei (Japanese Unexamined PatentPublication) 7-100186), and (B) a tape having a tensile strength of atleast 200 psi (about 14 kg/cm²), a drug/mm³ of 0.01 to 2 mg and anoptimum solubility to the drug, and having a composition comprisingabout 10 to 40% by weight of a physiologically acceptable thermoplasticpolymer, about 15 to 50% by weight of a saccharide, about 5 to 40% byweight of a physiologically acceptable plasticizer and about 0 to 20% byweight of a physiologically acceptable lubricant (Toku-Kai-Hei 5-220203)are known. Further, (C) a sheet-shaped solid pharmaceutical compositioncharacterized in that a solution or a suspension containing a substancehaving physiologically active action by the existence thereof in slightamounts is printed on, spread on, sprayed on, or injected into apharmaceutically acceptable sheet-shaped carrier (Toku-Kai-Hei 5-124954)is also known.

However, in the above-mentioned invention (A), it is described that “itis an object of this invention to provide an administration formationrapidly decomposing in water and individually formulated in a sheetform” (the publication, page 8, right column, [0028]), but whatcontrivance causes the formation to rapidly decompose is not describedat all. Although a drug is obtained in Example 2, merely “the drugdecomposes in the mouth” (the publication, page 10, left column, [0064])is only described, and details such as for the time for decomposition ofthe drug decomposes are not clear. In this Example 2, the temperature iselevated to 80° C. in preparation, so that a considerable period of timeis taken for cooling after mixing and the like, which causes adisadvantage in the manufacturing process. Further, in theabove-mentioned invention (B), sorbitol (lubricant) is used as oneuseful to enhance speeds of disintegration and dissolution of the tape.However, it is described that “for further assisting dissolution, adisintegrating agent, for example, cross caramelose Na type A, can beused in an amount of not exceeding about 10% by weight”, and this isconsidered because the use of only sorbitol sometimes results in aninsufficient disintegration rate. Furthermore, in this invention, thedrug tape is mounted on a dispenser, so that it is necessary to have adefinite tensile strength. Control for the tensile strength is thereforerequired in production, which is disadvantageous to efficiency in actualproduction. Still further, in the above-mentioned invention (C), thesubstance showing physiologically activity by the existence thereof inslight amounts (a drug: for example, 0.02 mg per unit, in the case ofmestranol) is utilized. The drug is effectively used in such slightamounts, so that the solution or suspension of the drug is printed on,spread on, sprayed on, or injected into the sheet-shaped carrier.However, this is time-consuming and not economical. Then, with respectto one shown in FIG. 1 of the published specification, not only slightsare provided, but also punching is performed with a punch, resulting incomplication of the process.

An object of the invention is to economically provide a film preparationhaving no disadvantages observed in the above-mentioned known filmpreparations, that is to say, rapidly dissolved, simply produced andeconomically obtained.

DISCLOSURE OF THE INVENTION

The present inventors have variously studied for obtaining a filmpreparation having sufficient rapid solubility by a simple process bythe addition of one ingredient. As a result, the present inventors havediscovered that the use of a drug, an edible polymer and amonosaccharide, a sugar alcohol or an oligosaccharide in combination cansolve the above-mentioned problems, thus completing the presentinvention.

That is to say, the present invention relates to (1) a rapidly solublefilm preparation mainly comprising a drug, an edible polymer and asaccharide, (2) the rapidly soluble film preparation described in (1),in which the content of the drug is from 0.01 to 50% by weight, that ofthe edible polymer is from 20 to 90% by weight, and that of thesaccharide is from 1 to 50% by weight, (3) the rapidly soluble filmpreparation described in (1), in which the drug is a compound enhancedin internal absorption by the conversion to a solid solution, (4) therapidly soluble film preparation described in (3), in which the compoundenhanced in internal absorption by the conversion to the solid solutionis nilvadipine, (5) the rapidly soluble film preparation described in(1), in which the edible polymer is one selected from the groupconsisting of synthetic polymers, cellulose derivatives and naturalpolymers, (6) the rapidly soluble film preparation described in (1) or(5), in which the edible polymer is at least one selected from the groupconsisting of poly(vinylpyrrolidone), hydroxypropyl methyl cellulose,hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose andethyl cellulose, (7) the rapidly soluble film preparation described in(1) or (2), in which the saccharide is one selected from the groupconsisting of monosaccharides, sugar alcohols and oligosaccharides, (8)the rapidly soluble film preparation described in (7), in which theoligosaccharide is starch syrup, (9) the rapidly soluble filmpreparation described in (8), in which the starch syrup is reducingmaltose starch syrup, (10) the rapidly soluble film preparationdescribed in (1), in which the drug is a compound which can be enhancedin internal absorption by the conversion to a solid solution, the ediblepolymer is one or more of poly(vinyl-pyrrolidone) and hydroxypropylcellulose, and an additional edible polymer, and the saccharide isstarch syrup, and (11) the rapidly soluble film preparation described in(10), in which the compound enhanced in internal absorption by theconversion to the solid solution is nilvadipine, the additional ediblepolymer is hydroxypropyl cellulose, and the starch syrup is reducingmaltose starch syrup.

As apparent from the above, the film preparation of the invention ischaracterized in that it is rapidly dissolved in the oral cavity and canbe taken without water, as a dosage form substitutive for a tablet.

The invention is described in detail below. The invention is the rapidlysoluble film preparation in which the drug is allowed to be contained ina film base comprising the edible polymer such as poly(vinylpyrrolidone), hydroxypropyl methyl cellulose, hydroxypropylcellulose, methyl cellulose, hydroxyethyl cellulose or ethyl cellulose,and the monosaccharide, the sugar alcohol or the oligosaccharide, andwhich is easily produced and has no conventional disadvantages asdescribed above.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph showing the elution rate of a rapidly soluble filmpreparation of the invention.

BEST MODE FOR CARRYING OUT THE INVENTION

The saccharides used in the invention include sugar alcohols such aserythritol, pentitol and hexitol, mono-saccharides (aldose and ketose)and oligosaccharides. Specifically, the sugar alcohols include xylitol,mannitol, D-sorbitol and reducing maltose starch syrup, themono-saccharides include glucose and fructose, the oligosaccharidesinclude maltose, lactose and sucrose, and themono-saccharide-oligosaccharides include starch syrup. Reducing maltosestarch syrup is particularly preferred. The compounding amount of thesaccharides in the film preparation of the present invention is from 1to 50% by weight, and preferably from 5 to 50% by weight. Less than 1%results in the insufficient rate of dissolution, whereas exceeding 50%raises a problem with regard to the shape retaining property ofproducts, although the rate of dissolution is increased. Many of thesaccharides have sweet tastes, and this is advantageous for the filmpreparations soluble in the mouth. Further, many of them also act asplasticizers, like starch syrup. Accordingly, when they are used, it isnot necessary to especially use plasticizers, of course, theplasticizers may be used as so desired. When sorbitol is used as thesaccharide, sorbitol sometimes deposits as crystallites on filmsurfaces. However, the drug effect and the others are not affected atall.

There is no particular limitation on the edible polymer which is acomponent of the film base of the invention, as long as it has filmforming ability and is edible. The edible polymers include syntheticpolymers, for example, poly(vinylpyrrolidone) (hereinafter described as“PVP”), carboxyvinyl polymers (hereinafter described as “CVPs”),polyvinyl alcohol (hereinafter described as “PVA”) and the like,cellulose derivatives, such as hydroxypropyl methyl cellulose(hereinafter described as “HPMC”), hydroxypropyl cellulose (hereinafterdescribed as “HPC”), hydroxyethyl cellulose (hereinafter described as“HEC”), methyl cellulose (hereinafter described as “MC”), ethylcellulose (hereinafter described as “EC”) and the like, and polymersobtained from natural products, for example, sodium alginate, dextran,casein, pullulan and the like. Particularly preferred are PVP and HPC.These substances can be used either alone or as a combination of two ormore of them.

The total compounding amount of the edible polymers in the filmpreparation is from 20 to 90% by weight, and preferably from 25 to 80%by weight in all.

For the rapidly soluble film preparations of the invention, aromatics,coloring matter, preservatives, antioxidants, stabilizing agents,surfactants, plasticizers and the like may be properly used ascomponents of the film bases, as so desired, in addition to theabove-mentioned substances.

There is no particular limitation on the drugs used in the invention, aslong as they can be orally administered. Specific examples thereofinclude calcium antagonists such as nilvadipine and nicardipine,β2-stimulants such as procaterol hydrochloride and fenoterolhydrobromide, oral antidiabetic drugs such as glibenclamide, somniferousdrugs such as brotizolam and triazolam, β-blockers such as arotinololhydrochloride and carteolol hydrochloride, therapeutic drugs for thecoronary vessels such as nicorandil, anesthetics such as dibucainehydrochloride, nonsteroidal anti-inflammatory drugs such as diclofenacsodium and indomethacin, and sedatives such as diphenhydraminehydrochloride and scopolamine hydrobromide.

As the drugs used in the invention, ones having no bitter tastes aresuitable. However, even ones having bitter tastes can be used in theinvention by masking such as microcapsulation. The compounding amount ofthe drugs in the film preparation is usually from 1 to 50% by weight,although it varies depending on the properties of the drugs.

The rapidly soluble film preparations of the invention are produced, forexample, by the following method.

Specified amounts of the edible polymer, saccharide and drug aredissolved in a solvent in which these substances are soluble, forexample, ethanol, and the resulting solution is spread on a liner filmand dried to obtain a film. The film is cut to a desired size, andhermetically packaged if necessary to provide a product. The dissolutionof the drug can be accelerated by heating to about 50 to about 60° C. inpreparing the solution. Further, when foams are developed in thesolution in preparing it, standing overnight or vacuum deaeration ispreferably conducted. There is no particular limitation on the solventused in preparing the solution, as long as it dissolves the respectivecompounding components. Either a single solvent or a combined solventmay be used. Specifically, the solvents include ethanol, a mixture ofethanol and water, and the like.

In the invention, it has been found that when the specified ediblepolymers are used, some kinds of drugs are enhanced in internalabsorption thereof. That is to say, for example, when the drug isnilvadipine, the use of poly-(vinylpyrrolidone) and/or hydroxypropylmethyl cellulose as the edible polymer(s) enhances the internalabsorption. This is considered to be caused by the formation of a goodsolid solution by nilvadipine with these polymers. In this case, thefilm preparation can be produced by the use of onlypoly-(vinylpyrrolidone) and/or hydroxypropyl methyl cellulose as theedible polymer(s), but an additional edible polymer can provide a betterfilm preparation. For example, in the case of nilvadipine, hydroxypropylcellulose is suitably used.

Specific examples of the drugs forming the solid solutions with theedible polymers include nifedipine, phenytoin, chloramphenicol,griseofulvin, sulfamethizole and the like, as well as nilvadipine.

EXAMPLES

The invention is described below in detail with reference to examples.These examples are not to be construed as limiting the invention.

Example 1

To a suitable amount of ethanol, 4.0 parts by weight of nilvadipine,76.0 parts by weight of HPC and 20.0 parts by weight of reducing maltosestarch syrup were added and dissolved by stirring. This was spread on apolyester liner film and dried to produce a film having a thickness ofabout 250 μm. The resulting film was cut to a square, 16 mm each side,thereby obtaining a film preparation rapidly soluble in the oral cavity.

Example 2

To a suitable amount of ethanol, 4.0 parts by weight of nilvadipine,72.0 parts by weight of HPC, 4.0 parts by weight of PVP and 20.0 partsby weight of reducing maltose starch syrup were added and dissolved bystirring. This was spread on a polyester liner film and dried to producea film having a thickness of about 250 μm. The resulting film was cut toa square, 16 mm each side, thereby obtaining a film preparation rapidlysoluble in the oral cavity.

Examples 3 to 6

According to formulations of Table 1, rapidly soluble film preparationswere obtained in the same manner as with Example 2.

TABLE 1 Examples Name of Component 3 4 5 6 Nilvadipine 4.0 4.0 4.0 4.0HPC 64.0 56.0 51.0 46.0 PVP 12.0 20.0 20.0 20.0 Reducing Maltose Starch20.0 20.0 25.0 30.0 Syrup Total 100.0 100.0 100.0 100.0

Example 7

To a suitable amount of ethanol, 4.0 parts by weight of nilvadipine,72.0 parts by weight of HPC, 4.0 parts by weight of HPMC and 20.0 partsby weight of reducing maltose starch syrup were added and dissolved bystirring. This was spread on a polyester liner film and dried to producea film having a thickness of about 250 μm. The resulting film was cut toa square, 16 mm each side, thereby obtaining a film preparation rapidlysoluble in the oral cavity.

Examples 8 to 14

According to formulations of Table 2, rapidly soluble film preparationswere obtained in the same manner as with Example 7.

TABLE 2 Name of Examples Component 8 9 10 11 12 13 14 Nilvadipine 4.04.0 4.0 4.0 4.0 4.0 4.0 HPC 64.0 56.0 51.0 46.0 56.0 56.0 56.0 HPMC 12.020.0 20.0 20.0 — — — MC — — — — 20.0 — — EC — — — — — 20.0 — HEC — — — —— — 20.0 Reducing Mal 20.0 20.0 25.0 30.0 20.0 20.0 20.0 tose StarchSyrup Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0

Example 15

To a suitable amount of ethanol, 20.0 parts by weight of nicardipinehydrochloride, 40.0 parts by weight of HPC, 20.0 parts by weight of PVPand 20.0 parts by weight of reducing maltose starch syrup were added anddissolved by stirring. This was spread on a polyester liner film anddried to produce a film having a thickness of about 250 μm. Theresulting film was cut to a square, 16 mm each side, thereby obtaining afilm preparation rapidly soluble in the oral cavity.

Examples 16 to 21

According to formulations of Table 3, rapidly soluble film preparationswere obtained in the same manner as with Example 15.

TABLE 3 Examples Name of Component 16 17 18 19 20 21 Fenoterol Hydro-5.0 4.0 — — — — Bromide Indomethacin — — 2.0 2.0 2.0 2.0 HPC 55.0 56.078.0 58.0 78.0 58.0 PVP 20.0 20.0 — — — 20.0 Reducing Maltose 20.0 —20.0 40.0 — 20.0 Starch Syrup D-Sorbitol — 20.0 — — 20.0 — 100.0 100.0100.0 100.0 100.0 100.0

Examples 22 and 23

According to formulations of Table 4, rapidly soluble film preparationswere obtained in the same manner as with Example 7.

TABLE 4 Examples Name of Component 22 23* Nilvadipine 4.0 4.0 PVP 76.020.0 EC — 56.0 Reducing Maltose 20.0 20.0 Starch Syrup Total 100.0 100.0*Ethanol:purifiedwater = 3:1

Example 24

To a suitable amount of an ethanol-purified water (2:1) mixture, 4.0parts by weight of nilvadipine, 6.0 parts by weight of HPMC and 20.0parts by weight of reducing maltose starch syrup were added anddissolved by stirring. This was spread on a polyester separate film anddried to produce a film having a thickness of about 250 μm. Theresulting film was cut to a square, 16 mm each side, thereby obtaining afilm preparation rapidly soluble in the oral cavity.

Examples 25 to 28

According to formulations of Table 5, rapidly soluble film preparationswere obtained in the same manner as with Example 24.

TABLE 5 Examples Name of Component 25 26 27 28* Nilvadipine 4.0 4.0 4.04.0 HPC — 56.0 — — PVP 20.0 — — — HPMC — 20.0 20.0 20.0 MC 56.0 — 56.0 —EC — — — 56.0 Reducing Maltose 20.0 20.0 20.0 20.0 Starch Syrup Total100.0 100.0 100.0 100.0 *Ethanol:purified water = 3:1

Example 29

To a suitable amount of a mixture of ethanol-purified water (2:1), 4.0parts by weight of nilvadipine, 38.0 parts by weight of PVP, 38.0 partsby weight of HPMC and 20.0 parts by weight of reducing maltose starchsyrup were added and dissolved by stirring. This was spread on apolyester liner film and dried to produce a film having a thickness ofabout 250 μm. The resulting film was cut to a square, 16 mm each side,thereby obtaining a film preparation rapidly soluble in the oral cavity.Examples 30 to 32

According to formulations of Table 6, rapidly soluble film preparationswere obtained in the same manner as with Example 29.

TABLE 6 Examples Name of Component 30 31 32* Nilvadipine 4.0 4.0 4.0 HPC36.0 — — PVP 20.0 20.0 20.0 HPMC 20.0 20.0 20.0 MC — 36.0 — EC — — 36.0Reducing Maltose 20.0 20.0 20.0 Starch Syrup Total 100.0 100.0 100.0*Ethanol:purified water = 3:1

Comparative Example 1

To a suitable amount of ethanol, 4.0 parts by weight of nilvadipine,76.0 parts by weight of HPC and 20.0 parts by weight of PVP were addedand dissolved by stirring. This was spread on a polyester liner film anddried to produce a film having a thickness of about 250 μm. Theresulting film was cut to a square, 16 mm each side, thereby obtaining afilm preparation rapidly soluble in the oral cavity.

Comparative Example 2

To a suitable amount of ethanol, 2.0 parts by weight of indomethacin and98.0 parts by weight of HPC were added and dissolved by stirring. Thiswas spread on a polyester liner film and dried to produce a film havinga thickness of about 250 μm. The resulting film was cut to a square, 16mm each side, thereby obtaining a film preparation rapidly soluble inthe oral cavity.

(Elution Test)

Test Method

In a 100-ml tall beaker, 100 ml of purified water is placed, and stirred(100 rpm) with a stirrer. One piece of sample (16 mm×16 mm) is placed ina cylindrical stainless steel basket, and put under the water in thebeaker. Then, the basket is fixed. After a definite period of time frominitiation of the test, 500 μl was sampled, and determined with theHPLC. Results are shown in FIG. 1.

Industrial Applicability

The film preparations of the invention are very easily produced, havehigh rapid solubility, are extremely high in practical use, and aresuitable for using as film preparations for oral administration.

1. A water soluble film preparation for oral administration comprisingnilvadipine, an edible polymer which is one or more ofpoly(vinylpyrrolidone) and hydroxypropyl cellulose, and anoligosaccharide which is reducing maltose starch syrup, and wherein thefilm preparation further comprises an additional edible polymer selectedfrom the group consisting of poly(vinylpyrrolidone), hydroxyprpyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethylcellulose and ethyl cellulose.